Investigators involved in public health research must conduct high-quality studies that advance scientific knowledge for the collective benefit of the public's health, while at the same time ensuring that the individual rights of human subjects are protected. Successful completion of the Human Genome Project provides greater opportunity to incorporate the study of genetic factors into public health research. Integration of DNA specimen collection into epidemiological studies of complex disorders, such as birth defects, is necessary to identify genetic risk factors that affect susceptibility to potentially modifiable environmental risk factors, but collection of DNA samples often heightens concerns about ethical issues. Some of these issues include ensuring informed consent in an ongoing study as new genetic risk factors and novel genetic technologies for study continue to be identified, achieving a balance between improving participation using incentives and avoiding coercion, ensuring confidentiality of individual genetic data, and considering when and how to report research results to study participants. We present a discussion of ethical issues addressed by investigators of the National Birth Defects Prevention Study, a multisite, population-based, case-control study of risk factors for birth defects, which has incorporated the study of genetic risk factors. Study participants include infants and young children whose parents consent on their behalf, increasing the complexity of the ethical issues. Discussion of these issues and the methods employed to ensure protection of human subjects might be helpful to other investigators working to integrate genetics into large epidemiological studies.